rs755622441

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004360.5(CDH1):​c.1783C>A​(p.Pro595Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P595R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

CDH1
NM_004360.5 missense

Scores

1
9
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58
Variant links:
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3835183).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH1NM_004360.5 linkuse as main transcriptc.1783C>A p.Pro595Thr missense_variant 12/16 ENST00000261769.10
CDH1NM_001317184.2 linkuse as main transcriptc.1600C>A p.Pro534Thr missense_variant 11/15
CDH1NM_001317185.2 linkuse as main transcriptc.235C>A p.Pro79Thr missense_variant 12/16
CDH1NM_001317186.2 linkuse as main transcriptc.-183C>A 5_prime_UTR_variant 11/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.1783C>A p.Pro595Thr missense_variant 12/161 NM_004360.5 P1P12830-1
ENST00000563916.1 linkuse as main transcriptn.263+1192G>T intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.00053
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;T;T;.;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Benign
0.074
D
MetaRNN
Benign
0.38
T;T;T;T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Pathogenic
3.0
M;.;.;.;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.6
D;.;.;.;D
REVEL
Uncertain
0.30
Sift
Benign
0.14
T;.;.;.;T
Sift4G
Benign
0.26
T;T;T;T;T
Polyphen
1.0
D;.;.;.;.
Vest4
0.54
MutPred
0.44
Gain of phosphorylation at P595 (P = 0.0657);Gain of phosphorylation at P595 (P = 0.0657);.;Gain of phosphorylation at P595 (P = 0.0657);.;
MVP
0.88
MPC
0.81
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.29
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68855975; API